The initial event in the life cycle of a virus is its interaction with receptors present on the surface of a cell. Understanding these interactions is important to our understanding of viral tropism, spread, and pathogenesis. The human polyomavirus, JCV, is the etiological agent of the fatal central nervous system (CNS) demyelinating disease, progressive multifocal leukoencephalopathy (PML). JCV has also been associated with several human tumors, including oligoastrocytoma and medulloblastoma. Following primary infection, JCV establishes a lifelong persistent infection in kidney and lymphoid tissues. In a minority of individuals, the virus spreads to the CNS, infecting both oligodendrocytes and astrocytes. The mechanisms that restrict JCV tropism for these cells and tissues and the mechanisms that allow for the spread of JCV from the periphery to the CNS are not understood. Our laboratory has been studying early events in the life cycle of JCV. We have determined that: 1. an N-linked glycoprotein containing terminal alpha (2-6) linked sialic acid is a critical component of the JCV receptor; 2. JCV and the related polyomavirus, SV40, do not share receptor specificity; and, 3. JCV, unlike SV40, enters cells by clathrin dependent receptor mediated endocytosis. The long term goals of our research are to define the role of virus receptors in mediating infection of cells and in determining viral tropism, spread, and pathogenesis in the infected host. Our working hypothesis, which is based on our previous work, is that JCV receptor interactions are critical determinants of viral entry, tropism, and spread within the host. We will address this hypothesis by asking the following questions: 1. What is the identity of the JCV receptor? 2. What are the cell and tissue distributions of JCV receptors? and 3. How does JCV penetrate the plasma membrane and target its genome to the nucleus? The data resulting from these studies will yield novel insights into the pathogenesis of JCV induced disease and may lead to novel therapies to prevent or treat these diseases.